PENGARUH KARAKTERISTIK PERUSAHAAN TERHADAP PENGUNGKAPAN ASPEK-ASPEK TANGGUNG JAWAB SOSIAL (TJSL) (Studi Empiris pada Perusahaan Pertambangan dan Manufaktur yang Terdaftar di Bursa Efek Indonesia)

Tujuan dari penelitian ini adalah untuk mengetahui pengaruh ukuran perusahaan dan leverage terhadap pengungkapan seluruh dan masing-masing aspek tanggung jawab sosial dan lingkungan (TJSL) pada perusahaan pertambangan dan manufaktur yang terdaftar di Bursa Efek Indonesia (BEI) tahun 2004- 2007 . Pengujian penelitian ini dengan menggunakan analisis regresi berganda. Hasil penelitian menunjukkan bahwa pengungkapan TJSL meningkat dari tahun ke tahun, proporsi tingkat pengungkapan yang tertinggi pada perusahaan pertambangan yaitu pada aspek lingkungan, sedangkan pada perusahaan manufaktur yaitu pada aspek umum. Selanjutnya, hasil penelitian menunjukkan bahwa ukuran perusahaan berpengaruh positif terhadap pengungkapan seluruh dan masing-masing aspek TJSL baik pada perusahaan pertambangan maupun manufaktur sedangkan leverage berpengaruh negatif terhadap pengungkapan seluruh dan masing-masing aspek TJSL baik pada perusahaan pertambangan maupun manufaktur. Kata Kunci: ukuran perusahaan, leverage, pengungkapan aspek-aspek TJS

Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells

The idea that conversion of glucose to ATP is an attractive target for cancer therapy has been supported in part by the observation that glucose deprivation induces apoptosis in rodent cells transduced with the proto-oncogene MYC, but not in the parental line. Here, we found that depletion of glucose killed normal human cells irrespective of induced MYC activity and by a mechanism different from apoptosis. However, depletion of glutamine, another major nutrient consumed by cancer cells, induced apoptosis depending on MYC activity. This apoptosis was preceded by depletion of the Krebs cycle intermediates, was prevented by two Krebs cycle substrates, but was unrelated to ATP synthesis or several other reported consequences of glutamine starvation. Our results suggest that the fate of normal human cells should be considered in evaluating nutrient deprivation as a strategy for cancer therapy, and that understanding how glutamine metabolism is linked to cell viability might provide new approaches for treatment of cancer

Constitutive activation of the PI3K-Akt-mTORC1 pathway sustains the m.3243 A > G mtDNA mutation

Mutations of the mitochondrial genome (mtDNA) cause a range of profoundly debilitating clinical conditions for which treatment options are very limited. Most mtDNA diseases show heteroplasmy – tissues express both wild-type and mutant mtDNA. While the level of heteroplasmy broadly correlates with disease severity, the relationships between specific mtDNA mutations, heteroplasmy, disease phenotype and severity are poorly understood. We have carried out extensive bioenergetic, metabolomic and RNAseq studies on heteroplasmic patient-derived cells carrying the most prevalent disease related mtDNA mutation, the m.3243 A > G. These studies reveal that the mutation promotes changes in metabolites which are associated with the upregulation of the PI3K-Akt-mTORC1 axis in patient-derived cells and tissues. Remarkably, pharmacological inhibition of PI3K, Akt, or mTORC1 reduced mtDNA mutant load and partially rescued cellular bioenergetic function. The PI3K-Akt-mTORC1 axis thus represents a potential therapeutic target that may benefit people suffering from the consequences of the m.3243 A > G mutation

Pyruvate Carboxylase Is Critical for Non-Small-Cell Lung Cancer Proliferation

Anabolic biosynthesis requires precursors supplied by the Krebs cycle, which in turn requires anaplerosis to replenish precursor intermediates. The major anaplerotic sources are pyruvate and glutamine, which require the activity of pyruvate carboxylase (PC) and glutaminase 1 (GLS1), respectively. Due to their rapid proliferation, cancer cells have increased anabolic and energy demands; however, different cancer cell types exhibit differential requirements for PC- and GLS-mediated pathways for anaplerosis and cell proliferation. Here, we infused patients with early-stage non-small-cell lung cancer (NSCLC) with uniformly 13C-labeled glucose before tissue resection and determined that the cancerous tissues in these patients had enhanced PC activity. Freshly resected paired lung tissue slices cultured in 13C6-glucose or 13C5,15N2-glutamine tracers confirmed selective activation of PC over GLS in NSCLC. Compared with noncancerous tissues, PC expression was greatly enhanced in cancerous tissues, whereas GLS1 expression showed no trend. Moreover, immunohistochemical analysis of paired lung tissues showed PC overexpression in cancer cells rather than in stromal cells of tumor tissues. PC knockdown induced multinucleation, decreased cell proliferation and colony formation in human NSCLC cells, and reduced tumor growth in a mouse xenograft model. Growth inhibition was accompanied by perturbed Krebs cycle activity, inhibition of lipid and nucleotide biosynthesis, and altered glutathione homeostasis. These findings indicate that PC-mediated anaplerosis in early-stage NSCLC is required for tumor survival and proliferation

Cysteine and Folate metabolism are targetable vulnerabilities of metastatic colorectal cancer

With most cancer-related deaths resulting from metastasis, the development of new therapeutic approaches against metastatic colorectal cancer (mCRC) is essential to increasing patient survival. The metabolic adaptations that support mCRC remain undefined and their elucidation is crucial to identify potential therapeutic targets. Here, we employed a strategy for the rational identification of targetable metabolic vulnerabilities. This strategy involved first a thorough metabolic characterisation of same-patient-derived cell lines from primary colon adenocarcinoma (SW480), its lymph node metastasis (SW620) and a liver metastatic derivative (SW620-LiM2), and second, using a novel multi-omics integration workflow, identification of metabolic vulnerabilities specific to the metastatic cell lines. We discovered that the metastatic cell lines are selectively vulnerable to the inhibition of cystine import and folate metabolism, two key pathways in redox homeostasis. Specifically, we identified the system xCT and MTHFD1 genes as potential therapeutic targets, both individually and combined, for combating mCRC

Trophic Relationships and Food Supply of Heterotrophic Animals in the Pelagic Ecosystem of the Black Sea

During recent decades, the Black Sea has been affected by many negative factors that strongly changed the condition of its ecosystem. Especially trophic relationships in the Black Sea pelagic system became very vulnerable influencing the food supply, productivity and abundance of many species and populations of this marine basin. Food is one of most important link between biota and its environment. In this monograph, the role and variability of trophodynamic processes that effect the well-being (health) of main heterotrophic components of ecosystem were analysed in detail for a few key species as indicators for estimation of ecosystem condition in whole. These are most significant mass species of the Black Sea pelagic ecosystem. Among copepods this is Calanus euxinus that dominates the mesozooplankton which makes up the fodder base of planktivorous fishes. Among gelatinous these are medusa Aurelia aurita and the alien ctenophores Mnemiopsis leidyi and Beroe ovata which affected strongly mesozooplankton composition. Lastly among fishes the anchovy Engraulis encrasicolus ponticus and sprat Sprattus sprattus phalericus that dominate small pelagic fishery. We considered in this monograph: • Diel feeding behaviour, in situ feeding rate of Calanus euxinus and impact of mesozooplankton on primary production and phytoplankton biomass. • The effect of vertical migrations on energy budget and its components in C. euxinus; metabolic substrates used in catabolic processes under both aerobic and hypoxic conditions, the role of reserve lipids and effect of abiotic factors on individual growth and population structure of this species. • The intensity and efficiency of ingestion and energy transformation in three gelatinous species ( jellyfish Aurelia aurita, ctenophores Mnemiopsis leidyi and Beroe ovata) and their predatory impact on zooplankton community. • Nutritional condition and food supply of anchovy and sprat in the close interaction with natural biotic and abiotic and anthropogenic factors. • Tendencies in this interaction during long time space: since 1960 s till present years. • Estimation of population condition of these species and its long-term change. This monograph is the collective work of Ukrainian and Turkish scientists studying complex hydrobiological problems of the Black Sea. Its aim is to reveal the significance of nutritional factors on the ecology of Black Sea biota, including changes which have already occurred, as well as offering some insight into changes that may happen in the future. Our joint investigations started in the first half of the 1990s, when conditions for the close cooperation of researchers from the two countries were suitable after the collapse of the Soviet era. This spirit continues to the present day. Professor Ümit Unluata, Director of Erdemli Institute of Marine Sciences (Middle East Technical University, Ankara) was of paramount importance in organising and fostering the work undertaken. We would like to devote this monograph to the memory of him, who died so prematurely. We are also grateful to Academician Professor V. N. Eremeev, Director of the Sevastopol Institute of Biology of the Southern Sea (National Academy of Sciences of Ukraine), and to the directors of Erdemli Institute of Marine Sciences (Professor Ilkay Salihoglu, Professor Sukru Besiktepe and Professor Ferit Bingel) who also made significant contributions to the Ukrainian–Turkish collaboration. We are grateful to Dr Bill Parr from the Black Sea Ecosystem Recovery Project for his valuable efforts in improving earlier drafts. All these investigations were carried out within the framework of the following five NATO linkage-grants: • Pelagic animal food supply in the unstable Black Sea environment, • Will the new alien ctenophore Beroe ovata control the plankton community in the Black Sea? • Grazing, growth and production of Calanus euxinus in the Black Sea, • Bioindicators for assessment of Black Sea ecosystem recovery, • Adaptability and vulnerability of marine species in changing environments. And four TUBITAK - NASU joint projects: • Quantification of the recent ctenophore invader Beroe ovata impact in the Black Sea • Monitoring of the Black Sea anchovy and sprat, • Salinity tolerance as a key factor of invasion success of the copepods of Calanus genus into the Sea of Marmara, • Salinity tolerance as a key factor of invasion success of the mesozooplankton species into the Sea of Marmara. We hope that this publication will make a substantial contribution to future studies of the Black Sea ecosystem and offers further understanding of those features regulating biological processes in this unique marine basin

Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer

During tumorigenesis, the high metabolic demand of cancer cells results in increased production of reactive oxygen species. To maintain oxidative homeostasis, tumor cells increase their antioxidant production through hyperactivation of the NRF2 pathway, which promotes tumor cell growth. Despite the extensive characterization of NRF2-driven metabolic rewiring, little is known about the metabolic liabilities generated by this reprogramming. Here, we show that activation of NRF2, in either mouse or human cancer cells, leads to increased dependency on exogenous glutamine through increased consumption of glutamate for glutathione synthesis and glutamate secretion by xc-antiporter system. Together, this limits glutamate availability for the tricarboxylic acid cycle and other biosynthetic reactions creating a metabolic bottleneck. Cancers with genetic or pharmacological activation of the NRF2 antioxidant pathway have a metabolic imbalance between supporting increased antioxidant capacity over central carbon metabolism, which can be therapeutically exploited

Hyperpolarised 13C MRI: a new horizon for non-invasive diagnosis of aggressive breast cancer

Hyperpolarised 13C MRI (HP-MRI) is a novel imaging technique that allows real-time analysis of metabolic pathways in vivo. 1 The technology to conduct HP-MRI in humans has recently become available and is starting to be clinically applied. As knowledge of molecular biology advances, it is increasingly apparent that cancer cell metabolism is related to disease outcomes, with lactate attracting specific attention. 2 Recent reviews of breast cancer screening programs have raised concerns and increased public awareness of over treatment. The scientific community needs to shift focus from improving cancer detection alone to pursuing novel methods of distinguishing aggressive breast cancers from those which will remain indolent. HP-MRI offers the opportunity to identify aggressive tumour phenotypes and help monitor/predict therapeutic response. Here we report one of the first cases of breast cancer imaged using HP-MRI alongside correlative conventional imaging, including breast MRI

Energy Metabolism Characterization of a Novel Cancer Stem Cell‐Like Line 3AB‐OS

Cancer stem cells (CSC) have a central role in driving tumor growth. Since metabolism is becoming an important diagnostic and therapeutic target, characterization of CSC line energetic properties is an emerging need. Embryonic and adult stem cells, compared to differentiated cells, exhibit a reduced mitochondrial activity and a stronger dependence on aerobic glycolysis. Here, we aimed to comparatively analyze bioenergetics features of the human osteosarcoma 3AB‐OS CSC‐like line, and the parental osteosarcoma MG63 cells, from which 3AB‐OS cells have been previously selected. Our results suggest that 3AB‐OS cells depend on glycolytic metabolism more strongly than MG63 cells. Indeed, growth in glucose shortage or in presence of galactose or pyruvate (mitochondrial specific substrates) leads to a significant reduction of their proliferation compared to MG63 cells. Accordingly, 3AB‐OS cells show an increased expression of lactate dehydrogenase A (LDHA) and a larger accumulation of lactate in the culture medium. In line with these findings 3AB‐OS cells as compared to MG63 cells present a reduced mitochondrial respiration, a stronger sensitivity to glucose depletion or glycolysis inhibition and a lessened sensitivity to oxidative phosphorylation inhibitors. Additionally, in contrast to MG63 cells, 3AB‐OS display fragmented mitochondria, which become networked as they grow in glucose‐rich medium, while almost entirely loose these structures growing in low glucose. Overall, our findings suggest that 3AB‐OS CSC energy metabolism is more similar to normal stem cells and to cancer cells characterized by a glycolytic anaerobic metabolism

De novo MYC addiction as an adaptive response of cancer cells to CDK4/6 inhibition

Cyclin‐dependent kinases (CDK) are rational cancer therapeutic targets fraught with the development of acquired resistance by tumor cells. Through metabolic and transcriptomic analyses, we show that the inhibition of CDK4/6 leads to a metabolic reprogramming associated with gene networks orchestrated by the MYC transcription factor. Upon inhibition of CDK4/6, an accumulation of MYC protein ensues which explains an increased glutamine metabolism, activation of the mTOR pathway and blunting of HIF‐1α‐mediated responses to hypoxia. These MYC‐driven adaptations to CDK4/6 inhibition render cancer cells highly sensitive to inhibitors of MYC, glutaminase or mTOR and to hypoxia, demonstrating that metabolic adaptations to antiproliferative drugs unveil new vulnerabilities that can be exploited to overcome acquired drug tolerance and resistance by cancer cells